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Dear all,
I have a query related to calculation of dose.
I am working on nano-formulation of a drug which is available as a tablet form in the market.
It's pharmacokintic parameters, in tablet formulation for humans, are:
Tmax- 4hrs
Cmax- 300ng/ml
t1/2- 12hrs
Dose - 150mg (70kg human)
Dosing frequency-two times in a day (b.i.d)
Now my question is what concentration of the drug in the plasma should be targeted?
Cmax?
or
C last-Concentration before second dose?
Here i do not know EC50 concentration of the drug for targeting the plasma concentration.
Next question is how to scale down the dose to rat as my pharmacokinetic animal is rat?
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Rahul,
The target concentration to obtain totally depends on the PK-PD
relationship of the drug. If no interspecies scaling has been performed
previously with your drug, you can calculate the dose assuming a linear
relationship of body weight with V/F and a power relationship (0.75
power) with CL/F.
Cheers,
Rob ter Heine
---
Rob ter Heine, PhD, PharmD
Meander Medical Center, hospital Pharmacy
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Rahul,
> It's pharmacokintic parameters, in tablet formulation for humans, are:
> > Tmax- 4hrs
> Cmax- 300ng/ml
> t1/2- 12hrs
> Dose - 150mg (70kg human)
> From these secondary PK parameters you can make a guess at the primary PK parameters. With a Tmax of 4 h and Thalf of 12 h the conc extrapolated back to time zero from Cmax (300 ng/mL) could be about 500 ng/mL (and absorption half-life about 1 h). Assuming bioavailability of 100% (for example) the conc after an IV bolus dose would be 500 ng/mL=500 ug/L. Thus the volume of distribution (V) is about 150000 mcg/500 mcg=300 L/70kg and clearance (CL), calculated from V x ln(2)/Thalf, is about 17 L/h/70kg.
> Dosing frequency-two times in a day (b.i.d)
> The average steady state conc in humans is ratein/CL=(150mg/12h)/17 L/h which is about 0.7 mg/L or 700 mcg/L.
> Now my question is what concentration of the drug in the plasma should be targeted?
> > Cmax?
> or
> > C last-Concentration before second dose?
> The average steady state conc (700 mcg/L) is a first guess at the target concentration. Cmax and Cmin are rarely sensible first choices for the target conc unless you know something special about the pharmacodynamics (e.g. for some antibiotics it is empirically found that being above some magic minimum conc is usually sufficient).
> Here i do not know EC50 concentration of the drug for targeting the plasma concentration.
> If you looked for PKPD info in humans or non-human species you might find an estimate there. But at this first stage of making guesses for suitable doses for the rat I think aiming at the human average steady state conc would get you started. This is the approach that is typically applied (in reverse) when trying to guess human doses from rats.
> Next question is how to scale down the dose to rat as my pharmacokinetic animal is rat?
Most of the differences between rats and humans are explained by differences in size (e.g. see Teitelbaum et al. 2010) so a first step is to apply allometric theory (see Holford 1996 for basic concepts and Savage et al. 2008 for the theory and its refinements):
Vrat L = V L/70kg x (WTrat/70kg)^1
CLrat L/h = CL L/h/70kg x (WTrat/70kg)^(3/4)
There are often quite big differences in PK between species that are not predictable. Allometry cannot predict species differences in V or CL that are not directly associated with size. However, even when other things, such as in vitro enzyme activity in the different species, are taken into account then the predictions are often not much better (see Teitelbaum again). So don't be surprised if the rat PK turns out to be different from these human derived guesses.
Best wishes,
Nick
Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996;30(5):329-32.
Savage VM, Deeds EJ, Fontana W. Sizing up allometric scaling theory. PLoS Comput Biol. 2008;4(9):e1000171.
Teitelbaum Z, Lave T, Freijer J, Cohen AF. Risk assessment in extrapolation of pharmacokinetics from preclinical data to humans. Clin Pharmacokinet. 2010;49(9):619-32.
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Dear Sir,
Many thanks for your explanation.
Still i have one doubt.
As you explained how to get an idea about Css average and you suggested to target this concentration rather than Cmax or Clast.
In order to calculate rat dose using allometric equation i found a factor 4 to be multiplied in to the human dose (mg/kg) e.g. if human dose is 150 mg for 70 kg human (150/70=2.1 mg/kg)
So rat dose will be approx. 4*2.1=8.4 mg/kg
Will this dose of rat be sufficient to produce Css average (700ng/ml ) concentration in plasma ? or
I have to optimize rat dose without applying allometry to produce Css average concentration as predicted from human will suffices the purpose.
Eagerly waiting for your expert comment.
Regards,
Rahul vats
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Rahul,
> In order to calculate rat dose using allometric equation i found a factor 4 to be multiplied in to the human dose (mg/kg) e.g. if human dose is 150 mg for 70 kg human (150/70=2.1 mg/kg)
>
> So rat dose will be approx. 4*2.1=8.4 mg/kg
> > Will this dose of rat be sufficient to produce Css average (700ng/ml ) concentration in plasma ? o
The allometric formulas for calculating the rat doses are:
Vrat L = V L/70kg x (WTrat/70kg)^1
CLrat L/h = CL L/h/70kg x (WTrat/70kg)^(3/4)
I used these and worked out that you must have been using a WTrat of 225 g in order to find a ratio of mg/kg doses of 4 (see table below).
The dose of 8.4 mg/kg every 12 h in the rat would be predicted to have an average steady state conc of 700 mcg/L based on allometry and size alone. Note however that the human half-life (12.2 h with these values of CL and V) is 4 times longer than the rat prediction (2.9 h). You should consider more frequent dosing in the rat if you also want to match the peak to trough ratio expected in humans.
Good luck!
Nick
WTrat
0.224598 kg
WThuman
70 kg
human V 300 L/70kg
human CL
17 L/h/70kg
human Thalf 12.2 h
rat V
0.962562 L/rat
rat CL 0.229182 L/h/rat
rat Thalf 2.9 h
target conc 700 mcg/L
loading rat 673.7937 mcg
maintenance rat 160.4271 mcg/h
8.57143 mg/kg/12 h
maintenance human 2.142857 mg/kg/12h
rat/human 4
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